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RAGE against the cancer machine
SCIENCE AND MEDICINE
The hygiene hypothesis gains further momentum in childhood asthma Children who had had two or ew epidemiological data premore upper respiratory tract infecsented at the 96th International tions, such as rhinitis, had the risk of Conference of the American doctor-diagnosed Thoracic Society asthma reduced from (Toronto, Canada; 6·3% to 3·2% at age 7. May 5–10) further If the child’s parents strengthen the hypothehad a history of asthma sis that exposure to viral the reduction was even infections or endotoxins greater (10·3% to in early childhood is 4·7%). protective against the Conversely, children development of asthma. with more than two Sabina Illi (University lower respiratory tract Children’s Hospital, infections—in this age Charité, Berlin, group most likely due to Germany) presented respiratory syncytial results from the virus—had a higher risk Multicentre Allergy of developing asthma Study group. 1314 chil- Don’t wash the dog! (odds ratio 1·96 dren were followed from [CI 1·04–3·71]). birth to 7 years, and the number and Sami Remes (University of type of infections were assessed by Arizona, Tucson, AZ, USA) reasquestionnaire.
sured parents that pets are doing more good than harm if they are kept from the day that the child is born. In their cohort of 1246 children, children with dogs and no parental history of asthma were less likely to develop frequent wheezing (adjusted hazard ratio 0·53). There was, however, no protective effect if either parent had asthma. Anne Wright from the same group of investigators explains that the rationale behind the hygiene hypothesis is that exposure to certain types of infectious agents and endotoxins is essential for maturation of dendritic cells and production of interleukin12 (a type-1 cytokine), and that less exposure leads to an imbalance of type-1 and type-2 immune responses.
RAGE against the cancer machine
Experts tackle mysteries of chronic pelvic pain
The Image Bank
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B
locking the interaction between two proteins that regulate neural growth in the developing brain may provide a new way of suppressing tumour growth and metastasis, according to Anne Marie Schmidt (Columbia University, New York, NY, USA) and colleagues. One of the proteins, RAGE (receptor for advanced glycation end products), initiates several key cell-signalling pathways when activated by various ligands (including the protein amphoterin). In the embryonic brain, RAGE colocalises with amphoterin at the leading edge of advancing neurites, suggesting that the receptor-ligand pair contribute to the invasiveness of developing neurons and, by implication, to tumour growth and invasiveness too. Blockade of the RAGE-amphoterin pathway inhibited the growth and motility of both implanted and spontaneously occurring tumours (Nature 2000; 405: 354–60). The authors showed this using a number of different murine models: tumour growth was inhibited by antibodies against RAGE or amphoterin in athymic mice implanted with rat C6 glioma cells, as well as in mice implanted with glioma cells transfected with defective forms of RAGE; blockade of RAGE-amphoterin also suppressed the spontaneous appearance of papillomas in
THE LANCET • Vol 355 • May 20, 2000
mice overexpressing the v-Ha-ras oncogene, and prevented distant metastases from Lewis lung carcinoma. Schmidt and co-workers also showed that RAGE-amphoterin acts through three mitogen-activated protein kinase (MAPK) signalling molecules. “All three MAPK modules can act as relay stations for the regulation of growth, motility, and invasion”, say Lance Liotta and Timothy Clair (National Institute of Health, Bethesda, MD, USA) in an accompanying News and Views article (Nature 2000; 405: 287–88). This explains “how blocking RAGE will suppress all three components of the malignant phenotype”, they suggest. Schmidt claims that RAGE could be used as a target for therapeutic strategies to suppress local tumour growth and distant metastases. Such therapies, she predicts, will probably be used to “enhance other anti-tumour strategies, such as those designed to diminish neovascularisation, proliferation, and evasion of host-immune response”. In signal-transduction therapy, add Liotta and Clair, “the trick is to find a rheostat in the cell’s circuitry that is not bypassed by collateral or compensatory paths. The RAGEamphoterin pathway may well fulfil these criteria.” Dorothy Bonn
Sabine Kleinert
t the first UK meeting of the International Pelvic Pain Society (London, UK; May 13), delegates from a variety of disciplines pooled their expertise to discuss why 61% of women with chronic pelvic pain remain undiagnosed. Victoria Grace (University of Canterbury, Christchurch, New Zealand) challenged doctors to retain a perspective on psychological models of causation that are often perceived as patronising or demeaning. This theme was followed up in the presentations on pelvic congestion, a syndrome described by Richard Beard (Northwick Park Hospital, Harrow, UK) as a clear example of the interaction between psyche and soma. He prosposed that pelvic congestion, which accounts for over 70% of cases of “unexplained” chronic pelvic pain, is a stress-related ovarian-dependent functional disturbance of the reproductive organs. A simulated consultation between a patient with pelvic congestion and psychotherapist Amanda Smith (Northwick Park Hospital, Harrow, UK), showed the effectiveness of stress management in treating this condition, and highlighted the changes in attitude and behaviour encountered during psychotherapy.
A
Carole Gilling-Smith
1795
The hygiene hypothesis gains further momentum in childhood asthma Children who had had two or ew epidemiological data premore upper respiratory tract infecsented at the 96th International tions, such as rhinitis, had the risk of Conference of the American doctor-diagnosed Thoracic Society asthma reduced from (Toronto, Canada; 6·3% to 3·2% at age 7. May 5–10) further If the child’s parents strengthen the hypothehad a history of asthma sis that exposure to viral the reduction was even infections or endotoxins greater (10·3% to in early childhood is 4·7%). protective against the Conversely, children development of asthma. with more than two Sabina Illi (University lower respiratory tract Children’s Hospital, infections—in this age Charité, Berlin, group most likely due to Germany) presented respiratory syncytial results from the virus—had a higher risk Multicentre Allergy of developing asthma Study group. 1314 chil- Don’t wash the dog! (odds ratio 1·96 dren were followed from [CI 1·04–3·71]). birth to 7 years, and the number and Sami Remes (University of type of infections were assessed by Arizona, Tucson, AZ, USA) reasquestionnaire.
sured parents that pets are doing more good than harm if they are kept from the day that the child is born. In their cohort of 1246 children, children with dogs and no parental history of asthma were less likely to develop frequent wheezing (adjusted hazard ratio 0·53). There was, however, no protective effect if either parent had asthma. Anne Wright from the same group of investigators explains that the rationale behind the hygiene hypothesis is that exposure to certain types of infectious agents and endotoxins is essential for maturation of dendritic cells and production of interleukin12 (a type-1 cytokine), and that less exposure leads to an imbalance of type-1 and type-2 immune responses.
RAGE against the cancer machine
Experts tackle mysteries of chronic pelvic pain
The Image Bank
N
B
locking the interaction between two proteins that regulate neural growth in the developing brain may provide a new way of suppressing tumour growth and metastasis, according to Anne Marie Schmidt (Columbia University, New York, NY, USA) and colleagues. One of the proteins, RAGE (receptor for advanced glycation end products), initiates several key cell-signalling pathways when activated by various ligands (including the protein amphoterin). In the embryonic brain, RAGE colocalises with amphoterin at the leading edge of advancing neurites, suggesting that the receptor-ligand pair contribute to the invasiveness of developing neurons and, by implication, to tumour growth and invasiveness too. Blockade of the RAGE-amphoterin pathway inhibited the growth and motility of both implanted and spontaneously occurring tumours (Nature 2000; 405: 354–60). The authors showed this using a number of different murine models: tumour growth was inhibited by antibodies against RAGE or amphoterin in athymic mice implanted with rat C6 glioma cells, as well as in mice implanted with glioma cells transfected with defective forms of RAGE; blockade of RAGE-amphoterin also suppressed the spontaneous appearance of papillomas in
THE LANCET • Vol 355 • May 20, 2000
mice overexpressing the v-Ha-ras oncogene, and prevented distant metastases from Lewis lung carcinoma. Schmidt and co-workers also showed that RAGE-amphoterin acts through three mitogen-activated protein kinase (MAPK) signalling molecules. “All three MAPK modules can act as relay stations for the regulation of growth, motility, and invasion”, say Lance Liotta and Timothy Clair (National Institute of Health, Bethesda, MD, USA) in an accompanying News and Views article (Nature 2000; 405: 287–88). This explains “how blocking RAGE will suppress all three components of the malignant phenotype”, they suggest. Schmidt claims that RAGE could be used as a target for therapeutic strategies to suppress local tumour growth and distant metastases. Such therapies, she predicts, will probably be used to “enhance other anti-tumour strategies, such as those designed to diminish neovascularisation, proliferation, and evasion of host-immune response”. In signal-transduction therapy, add Liotta and Clair, “the trick is to find a rheostat in the cell’s circuitry that is not bypassed by collateral or compensatory paths. The RAGEamphoterin pathway may well fulfil these criteria.” Dorothy Bonn
Sabine Kleinert
t the first UK meeting of the International Pelvic Pain Society (London, UK; May 13), delegates from a variety of disciplines pooled their expertise to discuss why 61% of women with chronic pelvic pain remain undiagnosed. Victoria Grace (University of Canterbury, Christchurch, New Zealand) challenged doctors to retain a perspective on psychological models of causation that are often perceived as patronising or demeaning. This theme was followed up in the presentations on pelvic congestion, a syndrome described by Richard Beard (Northwick Park Hospital, Harrow, UK) as a clear example of the interaction between psyche and soma. He prosposed that pelvic congestion, which accounts for over 70% of cases of “unexplained” chronic pelvic pain, is a stress-related ovarian-dependent functional disturbance of the reproductive organs. A simulated consultation between a patient with pelvic congestion and psychotherapist Amanda Smith (Northwick Park Hospital, Harrow, UK), showed the effectiveness of stress management in treating this condition, and highlighted the changes in attitude and behaviour encountered during psychotherapy.
A
Carole Gilling-Smith
1795